Biomedical Polypeptides — A Wellspring of Pharmaceuticals

Abstract

Decades of peptide research have created a wide variety of biomedical polypeptides: hormones, neurotransmitters, antigenic protein fragments, synthetic peptides, enzyme substrates and inhibitors, chemotactic agents, and ionophoric agents. A major benefit arising from this research is the creation of a rich source of new pharmocophores from which drugs can be designed.

Regardless of their origin, all peptides address a common group of drug development problems. This chapter reviews some of these problems and the possibilities for development of new drugs from peptides.

The diverse activities of peptides arise from the types of amino acids, from their sequence in the peptide chain, and from the conformations of the peptide backbone. Sequences can be assigned different roles: message sequences, signal sequences, prohormone sequences, and stability sequences. Flexibility of the peptide chain gives rise to many conformations in solution, only a small number of which allow for favorable receptor interaction. Such bioactive conformations can be stabilized in constrained synthetic analogues of the peptide, improving potency, stability, and selectivity.

Although some natural peptides display sufficiently selective action and proteolytic stability to produce therapeutic actions in humans, many more peptides are degraded too rapidly or elicit a multitude of responses on pharmacologic administration. Chemists have discovered a variety of synthetic modifications which can dramatically improve proteolytic stability, potency, and selectivity. A number of synthetic peptides have now been developed which display useful therapeutic actions in humans, many of which can be administered by oral and intranasal routes.

Past research with native peptides developed a strong bias against the potential for either adequate peptide intestinal transport or adequate peptide blood-brain barrier permeability. Recent research suggests that both barriers may be surmountable.

The classic approach to pharmacologic control of endogenous peptide action would be with agonists and antagonists to the peptides. A variety of alternate approaches to control of endogenous peptide levels are offered by the peptide biosynthetic pathway: (1) blockage of posttranslational processing with selective enzyme inhibitors; (2) modulation of peptide release with agonists and antagonists to the natural peptide release factors and to the natural peptide release-inhibiting factors, and with selective enzyme inhibitors to posttranslational processing of these factors; and (3) enhancement of endogenous peptide levels by blocking degradation with selective enzyme inhibitors.

Peptides can also be developed to serve as proteinase inhibitors, synthetic vaccines, and as ionophoric antibiotics.

A wide variety of methods are available for synthesizing peptides of any size or structure: chemical synthesis, biological synthesis, and semisynthesis. In essence, all of the tools are in hand to develop novel therapeutic agents from peptides for both human and animal health maintenance.